MLL a SET domain histone methyltransferase that catalyzes
MLL associated
translocations are found in 70% of infant leukaemia’s less than 2 years of age1. Normally, the MLL gene encodes
for a SET domain histone methyltransferase that catalyzes histone H3 lysine 4
methylation at particular regions and in mixed lineage leukemia, the catalytic
SET domain responsible for H3K4 methyltransferase property is lost and the
remaining MLL protein is fused to a
variety of partners such as AF4, AF9, ENL and AF10 by chromosomal
translocations in a balanced manner which causes the overexpression of leukemia
promoting genes2.Various cellular proteins like
PI3K, GSK3?, mTOR, cyclin dependent kinases, histone deacetylases and histone
methyltransferases are targeted for the treatment of mixed lineage leukemia.
Keywords-Mixed
lineage leukemia, translocation,histone methyltransferase, apoptosis, differentiation
I. Introduction
Mixed Lineage Leukemia pathology associated with
haemopoetic cells is under a hot bebate from the last two decades. MLL
associated translocations are found in 70% of infant leukaemia’s under the age
of 2 years with a very poor prognosis1. Mixed lineage
leukemia display co-expression of lymphoid as well as myeloid antigens hence
infants with MLL translocation show both myeloid and lymphoid blast cell
population3. Normally, the
MLL gene encodes for a SET domain histone methyltransferase that catalyzes the
methylation of lysine 4 of histone H3 (H3K4) at particular regions 4. In MLL, the catalytic
SET domain responsible for H3K4 methyltransferase activity is lost and the
remaining MLL protein is fused to a
variety of partners such as AF4, AF9, AF10 and ENL by balanced chromosomal translocations
and rearrangements2. Amino terminal
portion of MLL protein is fused to fifty distinct binding partners 5.The fusion
products retain the abilty to locate gene specific recognition regions even after translocation and interact directly
or indirectly with other histone
methyltransferaes like DOTIL6. DOT1L
interacts with six unique MLL fusion proteins created by chromosomal translocations
i.e. MLL-AF4, MLL-AF9, MLL-ENL, MLL-AF10, SET-NUP214, CALM-AF107.The fusion
products gain the ability to recruit Dot1L to the aberrant gene regions and
increase the expression of genes responsible for promotion of leukaemia 8.There is still
lack of good quality therapeutics for mixed lineage leukemia due to lack of
small molecule inhibitors that will directly target MLL9.The focus of
the review will be on the recent published work as well as therapeutic targets
from the last 2 decades.
II.
PI3K as a therapeutic target of MLL
Recent
reports have shown that Simaltaneous inhibition of PI3K/mTOR has shows anticancer activity in MLL
rearranged leukaemias10. In vivo
PI3K/mTOR inhibition has shown to reduce
tumour progression and also shown to increase survival in MLL-AF9 xenograft
mouse model10.BEZ, rapamycin
and MK-2206 have shown good in vitro activity as well as have shown good
activity in mice tumour models by inhibiting PI3K, mTOR and AKT pathways10.
III.
CDK4/CDK6 as a therapeutic target of MLL
In
MLL there is a cell differentiation block which can be broken by using small
molecules like CDK6 inhibitors11.CDK6 as a
therapeutic target for mixed lineage leukemia was identified by Plakle et al.,
201412. PD-0332991 is a dual
inhibitor of CDK4/CDK6 which is clinical trials for treatment of breast cancers as well as
PD-0332991 have shown strong growth inhibition in MLL rearranged leukemic cells 12. Current
treatment of MLL is chemotherapy and allogenic stem cell transplantation in
selected cases13.
IV.
Small molecule inhibitors of histone deacetylases as treatment of MLL
It
has been shown recently that HDAC inhibitors induce apoptosis
in MLL rearranged cell by autophagy 14. Inhibition of
histone deacetylase by VPA (valproic acid) in cells harbouring MLL induced cell cycle arrest
(G1-phase) and apoptotic cell death in MLL-AF9 expressing cell lines15.
V.
Retinoic acid and Vitamin D as important drugs for MLL
MLL-AF9 expressing leukemic cell line MOLM-14
undergoes differentiation when exposed to ATRA or 1, 25-dihydroxyvitamin D316. Simultaneous
treatment of MLL cells with Retinoic acid and epidrug 5-azacytidine has shown
to inhibit growth of MLL positive
leukemic cells17
VI.
Glycogen Synthase kinase 3 is an important target to control MLL
Glycogen
Synthase kinase3 has shown to support
MLL leukemia proliferation18.GSK3 inhibition
has shown to induce G1 growth arrest and
cell death in MLL transformed cells18. GSK3-?
inhibition has shown to increase survival in mouse model of MLL associated leukaemic
18. Specific GSK-3 inhibitor
SB-415286 has been repored to inhibit growth by induction of apoptosis in leukemic cells19.
VII.Combination
of Sirt1 activators and DOT1L inhibitor for the treatment of mixed lineage
leukemia
Activation
of SIRT1 and at same time inhibition of DOTIL has been shown be an effective therapy for mixed lineage leukemia20.SIRT1
activation mediated silencing of the
MLL-AF9 leukemia has been shown to be enhanced by simultaneous DOT1L inhibition20.SIRT1 activator
SRT1720 in combination with DOTIL inhibitor augment has been reported to cause apoptosis induction in mixed lineage
leukemia cells20.
VIII. ?-catenin as a therapeutic target of MLL
It has been reported that Leukemic stem cells have a more self renewal and drug résistance property 21. ?-catenin establishes the growth of mixed
lineage leukemia Leukemic stem cells22. Reversal of LSC to PLSC has shown to significantly
reduces the growth of mixed lineage
leukemia cells by ?-catenin downregulation or suppression 23.
